Abstract
BackgroundIn a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients.MethodsThe study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference.ResultsNo difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa.ConclusionsThe reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov: NCT01666301
Highlights
In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability
The most recent history of ESAs has been signed by the development of long-acting compounds with distinct molecular structure compared with the original epoetin alfa and beta, such as Darbepoetin alfa (half-life 48.8 ± 5.2 hours after subcutaneous (s.c) administration) [6,7] and C.E.R.A. (Continuous erythropoietin receptor activator) (139 ± 20 hours after s.c administration) [8,9], resulting in the recommendation to clinicians to lengthen the administration interval, up to once monthly
Aware of the limits of the simulation tool, aiming at verifying our results in the clinical setting and in order to analyze the cellular kinetics of erythopoiesis under different therapeutic strategies, we studied the relationship between two relevant pharmacodynamic response parameters, hemoglobin and reticulocytes, under different ESAs (C.E.R.A and Darbepoetin alfa) and administration intervals in a collective of chronic HD patients
Summary
In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The ESAs therapy implicates a non-physiologic stimulation of the erythropoietic process and has been identified as one of the most influential causative factors of hemoglobin variability in HD patients. ESAs therapy induces intermittent peaks of plasmatic erythropoietin (EPO), as compared with the more stable concentration profile of endogenous EPO under the close feed-back loop between erythropoietin concentration and EPO-sensing and producing system acting in physiologic circumstances [1]. Several other aspects of the ESAs therapy may contribute to destabilize the hemoglobin profile over time, such as drug-related factors (pharmacokinetic and bioavailability) and the dose adjustment strategy (doses, dosage frequency) applied by the prescriber [2,3,4,5]. The most recent history of ESAs has been signed by the development of long-acting compounds with distinct molecular structure compared with the original epoetin alfa and beta, such as Darbepoetin alfa (half-life 48.8 ± 5.2 hours after subcutaneous (s.c) administration) [6,7] and C.E.R.A. (Continuous erythropoietin receptor activator) (139 ± 20 hours after s.c administration) [8,9], resulting in the recommendation to clinicians to lengthen the administration interval, up to once monthly
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
